S113: NATIONAL PEGASPARGASE-MODIFIED RISK-ORIENTED PROGRAM FOR PHILADELPHIA-NEGATIVE ADULT ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOBLASTIC LYMPHOMA (PH− ALL/LL). GIMEMA LAL 1913 FINAL RESULTS.
Authors: R. Bassan, S. Chiaretti, I. Della Starza, O. Spinelli, A. Santoro, L. Elia, M. S. De Propris, A. M. Scattolin, F. Paoloni, M. Messina, E. Audisio, L. Marbello, E. Borlenghi, P. Zappasodi, C. Vetro, G. Martinelli, D. Mattei, N. Fracchiolla, M. Bocchia, P. De Fabritiis, M. Bonifacio, A. Candoni, V. Cassibba, P. Di Bartolomeo, G. Latte, S. Trappolini, A. Guarini, A. Vitale, P. Fazi, M. Vignetti, A. Rambaldi, R. Foà
Journal: HemaSphere (2022)

Background: Pediatric-inspired chemotherapy is standard of care for younger adults with Ph− ALL/LL. An essential component of these regimens is pegaspargase, here incorporated into a national treatment program for patients 18-65 years. Aims: To assess in the GIMEMA Phase 2 LAL 1913 study the feasibility and efficacy of a pegaspargase-containing induction and consolidation regimen sustaining a risk-oriented strategy for adult Ph− ALL/LL (ClinicalTrials.gov ID NCT02067143). Methods: Our prior, reference 8-block chemotherapy protocol (Blood Cancer J 2020;10:119) was modified to include pegaspargase 2000 IU/m2 at courses 1 (d10), 2 (d8), 5 (d3, with HD-MTX) and 6 (d8), with dose reductions in patients >55 years (pegaspargase 1000 IU/m2). Serum drug activity was not assessed in this study. Responders were risk-stratified for allogeneic stem cell transplantation (SCT) or maintenance according to a mixed risk model based on WBC count, immunophenotype, genetics and post-remission molecular minimal residual disease (MRD): patients with high-risk (HR) features or MRD ≥ 10-4 at weeks 10-16 or positive at week 22 were eligible to SCT; standard-risk (SR) patients were eligible to maintenance. Results: Two hundred and three patients entered the study (median age 39.8 years; 139 B- and 64 T-phenotype). The complete remission (CR) rate was 91% (100% in T-ALL/LL), with a 3-year cumulative relapse incidence and non-relapse mortality of 24.2% and 12.6%, respectively; 60 patients underwent a SCT. Overall (OS), event-free (EFS) and disease-free (DFS) survival were 66.7% (95% CI, 60.1-74.1%), 57.7% (95% CI, 51.0-65.3%) and 63.3% (95% CI, 56.3-71.1%) at 3 years. HR class (n=95) and LL diagnosis (n=20) did not affect prognosis. T-cell phenotype (CR 100%, P=0.001; EFS 67.1%, P=0.038), age 18-40 years (EFS 72.6%, P<0.0001) and MRD <10-4 after courses 1 (55%: DFS 77.9%, P=0.023) and 3 (79%: DFS 75.2%, P=0.048) were prognostically favorable. One hundred and eighty-seven patients had pegaspargase at course 1 (92.1%, 11 delayed, 3 reduced), 154 at course 2 (84.6%; 11 delayed, 12 reduced), 110 at course 5 (83.9%; 2 delayed, 11 reduced) and 73 at course 6 (68.8%; 3 delayed, 7 reduced). Dose reductions and delays were related to high-risk profile (liver dysfunction/steatosis, obesity etc.) or treatment toxicity. Toxicity of grade 2 or more was mainly observed at course 1 (hepatic 12.8%, coagulation/thrombosis 3.2% [enoxaparin prophylaxis recommended with platelets >30-50], pancreatic 1.6%), contributing to an induction death in 3 patients (1.4%), but was rare afterwards. Image:Summary/Conclusion: This pegaspargase-based ALL regimen was safely applicable to the majority of study patients, resulting in 3-year OS, EFS and DFS rates >50% in a patient population aged 18-65. The results were more favorable in patients up to the age of 55, especially in those aged 18-40 years, and in those who achieved maximum MRD response regardless of age (Figure). Subsequently, a pegaspargase dosing algorithm based on patient age, body mass index, hepatosteatosis and selected toxicities at first or prior drug exposure was developed to minimize toxicity, and was used in a successor GIMEMA trial of sequential chemotherapy-blinatumomab for CD19+ adult B-ALL (EHA Congress 2021, abstract S114).